The role of epidermal growth factor receptor in chordoma pathogenesis: a potential therapeutic target

• Published in: The Journal of pathology Vol. 223; no. 3; pp. 336 - 346
• Main Authors: Shalaby, Asem, Presneau, Nadège, Ye, Hongtao, Halai, Dina, Berisha, Fitim, Idowu, Bernadine, Leithner, Andreas, Liegl, Bernadette, Briggs, Timothy RW, Bacsi, Krisztian, Kindblom, Lars-Gunnar, Athanasou, Nicholas, Amary, Maria Fernanda, Hogendoorn, Pancras CW, Tirabosco, Roberto, Flanagan, Adrienne M
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01.02.2011; Wiley
• Subjects: amplification; Antineoplastic Agents - pharmacology; Biological and medical sciences; Bone Neoplasms - genetics; Bone Neoplasms - metabolism; Bone Neoplasms - pathology; Cell Proliferation - drug effects; chordoma; Chordoma - genetics; Chordoma - metabolism; Chordoma - pathology; Diseases of the osteoarticular system; DNA Mutational Analysis - methods; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical - methods; EGFR; Enzyme Inhibitors - pharmacology; genetics; Humans; In Situ Hybridization, Fluorescence; Investigative techniques, diagnostic techniques (general aspects); Medical sciences; Mutation; Neoplasm Proteins - metabolism; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; polysomy; PTEN; Quinazolines; Receptor Protein-Tyrosine Kinases - metabolism; Receptor, Epidermal Growth Factor - antagonists & inhibitors; Receptor, Epidermal Growth Factor - genetics; Receptor, Epidermal Growth Factor - metabolism; Receptor, ErbB-2 - metabolism; Skull Base Neoplasms - metabolism; Tumor Cells, Cultured; Tumors of striated muscle and skeleton; Tyrphostins - pharmacology; Targeting; Pathogenesis; Targeted therapy; Diseases of the osteoarticular system; PTEN; Malignant tumor; Epidermal growth factor receptor; EGFR; Osteoarticular system; Amplification; Chordoma; Anatomic pathology; Growth factor receptor; polysomy; Genetics; PTEN Gene; Bone; Cancer; Tumor suppressor gene
• ISSN: 0022-3417; 1096-9896
• DOI: 10.1002/path.2818

Chordoma, the molecular hallmark of which is T (brachyury), is a rare malignant bone tumour with a high risk of local recurrence and a tumour from which metastatic disease is a common late event. Currently, there is no effective drug therapy for treating chordomas, although there is evidence that some patients respond to the empirical use of epidermal growth factor receptor (EGFR) antagonists. The aim of this study was to determine the role of EGFR in the pathogenesis of chordoma. Paraffin‐embedded material from 173 chordomas from 160 patients [sacro‐coccygeal (n = 94), skull‐based (n = 50), and mobile spine (n = 16)] was analysed by immunohistochemistry and revealed total EGFR expression in 69% of cases analysed. Of 147 informative chordomas analysed by FISH, 38% revealed high‐level EGFR polysomy, 4% high‐level polysomy with focal amplification, 18% low‐level polysomy, and 39% disomy. Phospho‐receptor tyrosine kinase array membranes showed EGFR activation in the chordoma cell line U‐CH1 and all of the three chordomas analysed. Direct sequencing of EGFR (exons 18–21), KRAS, NRAS, HRAS (exons 2, 3), and BRAF (exons 11, 15) using DNA from 62 chordomas failed to reveal mutations. PTEN expression was absent by immunohistochemistry in 19 of 147 (13%) analysed chordomas, only one of which revealed high‐level polysomy of EGFR. The EGFR inhibitor tyrphostin (AG 1478) markedly inhibited proliferation of the chordoma cell line U‐CH1 in vitro and diminished EGFR phosphorylation in a dose‐dependant manner, a finding supported by inhibition of phosphorylated Erk1/2. p‐Akt was suppressed to a much lesser degree in these experiments. There was no reduction of T as assessed by western blotting. These data implicate aberrant EGFR signalling in the pathogenesis of chordoma. This study provides a strategy for patient stratification for treatment with EGFR antagonists. Copyright © 2010 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.